A complicating factor in the treatment of advanced breast cancer is skeletal muscle wasting. Approximately 15- 40% of breast cancer patients show signs of skeletal muscle wasting, which contributes to weakness, fatigue and limits the ability of patients to tolerate anti-cancer medication, adversely affecting patient survival. For breast cancer patients, diagnosis and treatment of skeletal muscle wasting may be complicated by unique factors. Skeletal muscle wasting may be masked by high BMI caused by accumulation of adipose tissue in place of muscle tissue. Treatment is complicated by the presence of differing molecular subtypes including luminal, Her2 and basal-like breast cancers, which express varying levels of inflammatory cytokines and growth factors that may not only contribute to cancer progression, but also cause changes to muscle physiology. By understanding the molecular and cellular processes of skeletal muscle wasting in breast cancer, we may identify more effective targeted treatments to alleviate muscle wasting and enhance effectiveness anti-cancer therapies. CCL2 is a well-known regulator of macrophage recruitment during inflammation and breast cancer progression, and mediates muscle repair. We had previous shown that CCL2 is most highly expressed in basal-.like breast cancers, a particularly aggressive breast cancer subtype. In the MDA-MB231 model of basal-like breast cancer, tumoral CCL2 expression was localized to muscle tissues, corresponding to increased inflammation, and expression of LC3B, an autophagy marker, MuRF1 and Atrogin 1, protein degradation markers, which are hallmarks of muscle wasting. These phenotypes were reduced with CCL2 knockdown in the primary tumor. Treatment of myoblasts with increasing doses of CCL2 or tumor conditioned medium inhibited cell proliferation and myotube formation. Treatment of myotube cultures increased MuRF1, Atrogin-1 and LC3B expression. Cytokine array analysis of breast cancer cells and datamining analysis revealed significant associations between CCL2 and IL12 and IL6, inflammatory cytokines that may be important in skeletal muscle wasting. We hypothesize that increased CCL2 expression in breast tumors cooperates with IL6 or IL12 to promote skeletal muscle wasting.
2 aims are proposed.
Aim 1 is to determine the contribution of tumoral CCL2 to breast cancer associated skeletal muscle wasting relative to IL6 and IL12 using the 4T1 model of basal-like breast cancer.
Aim 2 is to determine the functional contribution of CCL2 to myotube atrophy and impairment of muscle regeneration, relative to IL6 and IL12 using 3D cell culture models. This multi-interdisciplinary project involves experts on breast cancer and muscle physiology. These pilot studies would provide justification for long-term studies investigating the role and mechanisms of these cytokines in breast cancer associated muscle wasting, with the long-term goal of developing targeted therapies to alleviate muscle wasting and enhance effectiveness of anti-cancer therapies for breast cancer patients.

Public Health Relevance

Skeletal muscle wasting is a common condition detected in breast cancer patients, which decreases tolerance to anti-cancer therapy, and is associated with decreased patient survival. This project seeks to understand how CCL2 cooperates with other inflammatory factors: CCL5, IL6 and IL12 to promote skeletal muscle wasting in breast cancer using animal models and cell culture models. This project seeks to characterize new biomarkers with the long-term goal of developing new targeted therapeutic strategies to alleviate muscle wasting and improve anti-cancer therapy for breast cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA227359-01A1
Application #
9656303
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Spalholz, Barbara A
Project Start
2019-02-01
Project End
2021-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Kansas
Department
Pathology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160